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Hundreds of scientific articles are published each year about risk factors for breast cancer and about prevention of the disease. However, the most basic questions about what we really know get very little attention. How much of the occurrence of breast cancer can be explained by our current knowledge? What can women do to reduce their risk? And where should we look for the remaining pieces of the puzzle?

Two weeks ago a federal inter-agency task force issued a report emphasizing the need to redouble research efforts focused on the prevention of breast cancer. And just last week another report claimed that between 12 and 18% of breast cancer deaths are attributable to alcohol consumption. These and many similar studies focus our attention on specific risk factors or possible risk factors. But rarely are we given a critical overview of what we actually know and how useful this information is for the prevention of breast cancer. As a result, there is widespread confusion on this most important question.

Breast cancer is the most commonly occurring cancer in women both in this country, as well as worldwide. In the U.S. breast cancer accounts for nearly one-in-three cancers among women.

Epidemiologic studies over the past 40 years have identified numerous risk factors for breast cancer, including: older age, an early age at menarche, a late age at first full-term birth, not having children, a family history of breast cancer in a first-degree relative, greater height, higher circulating estrogen levels, postmenopausal hormone use, breast density, history of breast biopsies, obesity (for postmenopausal breast cancer), and exposure to ionizing radiation.

Known risk factors for breast cancer are relatively weak, contributing only a small elevation in risk. Even having a family history of breast cancer in a first degree relative carries about a twofold increase in risk. And the more recently discovered breast density is the strongest with roughly a 4-fold increase in risk. Thus, these breast cancer risk factors are nothing like cigarette smoking as a risk factor for lung cancer, where a current smoker has roughly a 15-fold increased risk compared to that of someone who never smoked, and a heavy smoker might have a 40 or 50-fold increased risk. Smoking accounts for the vast majority of lung cancer cases. (The strongest risk factors for breast cancer are older age and being female: women between the ages of 65 and 69 have 15 times greater breast cancer incidence compared to women between the ages of 30 and 34, and women have more than one hundred times the incidence of breast cancer compared to men.)

The “classical” reproductive and hormonal risk factors are generally explained by the effects of exposure of breast tissue to ovarian hormones, primarily estrogen but also progesterone. The greater the interval between menarche and menopause, the greater the number of menstrual cycles with spikes in exposure to these hormones. Following menopause, the main source of estrogen is from fat deposits, and this is believed to explain the association of obesity with postmenopausal breast cancer. Finally, current or recent use of postmenopausal hormones modestly increases the risk of postmenopausal breast cancer.

The protective effect of an early pregnancy is thought to be due to the fact that a first, full-term pregnancy stimulates the full differentiation of the cells lining the milk ducts, where most breast cancers arise.

Thus, from the point of view of reducing breast cancer risk, having a later onset of menstruation followed by an early pregnancy and a large number of children is beneficial. This was the pattern 150 years ago in this country and more recently in Asia, where rates of breast cancer have been about one-fifth of rates in the U.S.

An understanding of the hormonal nature of breast cancer has led to the development of highly effective treatments for the most common form of breast cancer in postmenopausal women.

Unfortunately, our extensive knowledge about risk factors affords little basis for women to reduce their risk, since most of these factors (family history, reproductive factors, etc.) are not modifiable.

And this knowledge does not enable us to accurately predict who will develop breast cancer and who will not.

Furthermore, this knowledge does not fully account for changes in breast cancer incidence. For example, on the basis of known risk factors, one would expect women of the “baby boom” generation to have increasing rates of breast cancer due to delayed child-bearing, having fewer children, and greater use of hormone therapy. But, in fact, breast cancer rates among women of this generation have declined.

Regarding the possible impact of environmental exposures (in the more narrow sense, e.g., pesticides, industrial pollutants, etc.), studies to date have not yielded any strong signals. However, most studies have focused on exposures in adulthood rather than in earlier periods when susceptibility may be greater.

Over the past twenty years, thinking about the causes and prevention of breast cancer has advanced in important ways, and the picture has become much more complicated than the overly simple focus on the “classical” risk factors allows for.

First, the discovery of rare, high penetrance germ-line mutations of BRCA1 and BRCA2 identified a small subset of women with a very high life-time risk of breast and ovarian cancer. However, only 1-2 percent of breast cancer is accounted for by these mutations.

Second, there is an increasing awareness that experiences starting in the womb may influence future risk of disease, that there are “windows of vulnerability,” and that the timing of exposures may affect future risk. Such periods include: in utero exposure, puberty, and the period between menarche and a first full-term pregnancy. Thus, the timing of exposure to hormones and other factors at different points in the life-span can have very different effects. For example, obesity actually appears to be protective for premenopausal breast cancer, whereas it is a risk factor for postmenopausal breast cancer. Furthermore, follow-up of women exposed to the atomic bomb at Hiroshima showed that exposure during adolescence (during breast development) carried a much higher risk of breast cancer than exposure later in life. The association of adult height with increased risk suggests that exposures during childhood and early adolescence (possibly a calorie-dense diet) may influence the risk of breast cancer.

Third, researchers have focused on so-called gene-environment interactions, reasoning that some exposures that have relatively weak associations with breast cancer in the general population may have a much stronger effect in subgroups with a specific genetic make-up. This line of research has to date yielded few instances of important interactions.